Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation.
Multidrug resistance-associated protein 1 (MRP1) is a cysteinyl leukotriene (CysLT) export pump expressed on mast cells. CysLTs are crucial mediators in allergic airway disease. However, biological significance of MRP1 in allergic airway inflammation has not yet been elucidated. In this study, we sensitized wild-type control mice (mrp1(+/+)) and MRP1-deficient mice (mrp1(-/-)) to ovalbumin (OVA) and challenged them with OVA by aerosol. Airway inflammation and goblet cell hyperplasia after OVA exposure were reduced in mrp1(-/-) mice compared with mrp1(+/+) mice. Furthermore, CysLT levels in bronchoalveolar lavage fluid (BALF) from OVA-exposed mrp1(-/-) mice were significantly lower than those from OVA-exposed mrp1(+/+) mice. Levels of OVA-specific IgE, IL-4, and IL-13 in BALF were also decreased in OVA-exposed mrp1(-/-) mice. IgE-mediated release of CysLTs from murine bone marrow-derived mast cells was markedly impaired by MRP1 deficiency. Our results indicate that MRP1 plays an important role in the development of allergic airway inflammation through regulation of IgE-mediated CysLT export from mast cells.
Yoshioka
Masakata
M
Dept. of Respiratory Medicine, Juntendo Univ. School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan. seigo@juntendo.ac.jp
Sagara
Hironori
H
Takahashi
Fumiyuki
F
Harada
Norihiro
N
Nishio
Kazuto
K
Mori
Akio
A
Ushio
Hiroko
H
Shimizu
Kazue
K
Okada
Takenori
T
Ota
Mayumi
M
Ito
Yoichi M
YM
Nagashima
Osamu
O
Atsuta
Ryo
R
Suzuki
Toshihiro
T
Fukuda
Takeshi
T
Fukuchi
Yoshinosuke
Y
Takahashi
Kazuhisa
K
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D003545:Cysteine / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007073:Immunoglobulin E / Q000276:immunology / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D003545:Cysteine; D007073:Immunoglobulin E; D015289:Leukotrienes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010047:Ovalbumin; C112381:cysteinyl-leukotriene; C421109:multidrug resistance-associated protein 1